1. Field of the Invention
This invention relates to substituted imidazolyl-alkyl-piperazine and diazepine derivatives, the pharmaceutically acceptable salts thereof, methods of making these compounds, and pharmaceutical compositions containing these compounds. The compounds of this invention have calcium entry blocking activity with selectivity for cerebral blood vessels, and have protective activity against some of the deleterious effects resultant upon cerebral ischemia.
The compounds of this invention are useful for treating mammals having any of a variety of disease states, including:
diseases treated by direct neuronal protection, such as ischemia including focal and global ischemia, spinal injuries, head trauma, and neurological diseases such as Alzheimer's and Huntington's chorea;
diseases treated by inhibition of sodium ion, such as uraemic and hyponatraemic encephalopathy; and
diseases treated with calcium channel antagonists, including:
diseases treated by inhibiting cerebrovascular vasospasm and by cerebrovascular vasodilation, such as migraine, stroke, vasospasm due to subarachnoid hemorrhage, epilepsy or epileptic psychotic symptoms, and cerebrovascular ischemia induced by cocaine abuse; and PA1 cardiovascular diseases, such as hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia, thrombosis, embolism, and congestive heart failure such as chronic or acute cardiac failure; and PA1 ischemia of lower legs due to peripheral vascular disease, e.g., intermittent claudication; PA1 spasms of smooth muscle: such as the ureter, the bladder, uterine cramps, diuresis, and irritable bowel syndrome; and PA1 uses during surgery: such as bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis, or post operative hypertension. PA1 provided that when R.sup.3 is hydroxy, n is one or two; and PA1 diseases treated by inhibiting cerebrovascular vasospasm and by cerebrovascular vasodilation, such as migraine, stroke, vasospasm due to subarachnoid hemorrhage, epilepsy or epileptic psychotic symptoms, and cerebrovascular ischemia induced by cocaine abuse; and PA1 cardiovascular diseases, such as hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia, thrombosis, embolism, and congestive heart failure such as chronic or acute cardiac failure; and PA1 ischemia of lower legs due to peripheral vascular disease, e.g., intermittent claudication; PA1 spasms of smooth muscle: such as the ureter, the bladder, uterine cramps, diuresis, and irritable bowel syndrome; and PA1 uses during surgery: such as bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis, or post operative hypertension, PA1 the compound of Formula A where R.sup.1 is 4-methylphenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 0 and q is 0, is named "1-diphenylmethyl-4- (2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl! piperazine"; PA1 the compound of Formula A where R.sup.1 is 4-methylphenyl, R.sup.2 is hydrogen, R.sup.3 is hydrogen, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 0 and q is 0, is named "1-diphenylmethyl-4- (2-(4-methylphenyl)-1H-imidazol-4-yl)methyl!piperazin e"; PA1 the compound of Formula A where R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 0 and q is 0, is named "1-diphenylmethyl-4- 1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl!piperazin e"; PA1 the compound of Formula A where R.sup.1 is cyclohexyl, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is phenyl, R.sup.5 is 2,3-dimethoxyphenyl, m is 2, n is 2 and q is 2, is named "1- 3-phenyl-3-(2,3-dimethoxyphenyl)propyl!-4- 3-(2-cyclohexyl-5-methyl-1H -imidazol-4-yl)pentyl!piperazine"; PA1 the compound of Formula A where R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydroxy, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 1 and q is 0, is named "1-diphenylmethyl-4- 2-(2-phenyl-5-methyl-1H-imidazol-4-yl)-2-hydroxyethyl !piperazine"; PA1 the compound of Formula A where R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is 4-fluorophenyl, R.sup.5 is 4-fluorophenyl, m is 2, n is 0 and q is 3, is named "1- 4,4-di-(4-fluorophenyl)-butyl!-4- (2-phenyl-5-methyl-1H-imidazol-4-yl) -methyl!piperazine"; and PA1 the compound of Formula A where R.sup.1 is 2,4-dihydroxyphenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 3, n is 0 and q is 0, is named "1-diphenylmethyl-4- (2-(2,4-dihydroxyphenyl)-5-methyl-1H-imidazol-4-yl)-m ethyl!diazepine". PA1 diseases treated by inhibiting cerebrovascular vasospasm and by cerebrovascular vasodilation, such as migraine, stroke, vasospasm due to subarachnoid hemorrhage, epilepsy or epileptic psychotic symptoms, and cerebrovascular ischemia induced by cocaine abuse; and PA1 cardiovascular diseases, such as hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia, thrombosis, embolism, and congestive heart failure such as chronic or acute cardiac failure; and PA1 ischemia of lower legs due to peripheral vascular disease, e.g., intermittent claudication: PA1 spasms of smooth muscle: such as the ureter, the bladder, uterine cramps, diuresis, and irritable bowel syndrome; and PA1 uses during surgery: such as bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis, or post operative hypertension.
2. Background Information and Related Art
Substituted piperazines have been described as having a variety of pharmaceutical activities.
For example, U.S. Pat. No. 3,362,956 and its CIP 3,491,098, disclose a series of substituted piperazines to be useful as tranquilizers, sedatives, adrenolytic agents, hypothermic agents, anti-convulsants, hypotensive agents and cardiovascular agents. For example, in the '956 patent, compounds of the formula: ##STR2## wherein R.sup.1 is a lower-alkyl, hydroxy-lower alkyl, phenyl or substituted-phenyl, phenyl-lower-alkyl, or substituted-phenyl-lower-alkyl, benzhydryl or substituted benzhydryl, phenyl-lower-alkenyl or substituted-phenyl- lower-alkenyl, or pyridyl radical; R.sup.2 is hydrogen or from one to two lower-alkyl radicals; Y is lower-alkylene of from one to six carbon atoms; and Het is a heterocyclic radical selected from the group consisting of bicyclic aromatic nitrogen heterocyclic radicals having fused five and six membered rings and containing from two to three ring nitrogen atoms which can be in any position of the two rings, for example, radicals derived from indazole (e.g. 2-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole), pyrrolo 2,3-d!-pyrimidine, benzimidazole and pyrido 2,1-c!-s-triazole; a benz g!-3-indolyl radical; a 4(5)-imidazolyl radical; a 3-thianaphthenyl radical; a 3-quinolyl radical; a 3,4-dihydro-1-isoquinolyl radical; or 1,2,3,4-tetrahydro-1-isoquinolyl radical or such heterocyclic radicals substituted in any available position by from one to three substituents, defined hereinafter as R.sup.2, for example methyl ethyl propyl and isobutyl; lower-alkoxy, for example, methoxy, ethoxy, propoxy, and butoxy; halogen, including fluorine, chlorine, bromine, and iodine; lower-alkylmercapto, for example, methylmercapto, ethylmercapto, propylmercapto, and isobutylmercapto; lower-alkylsulfinyl, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, and isobutylsulfinyl; lower-alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl; trifluoromethyl; hydroxy; methylenedioxy; or ethylenedioxy, wherein the lower-alkyl moiety of the said substituents contain from one to four carbon atoms; are disclosed.
In the '098 patent compounds of the formula: ##STR3## wherein R is hydrogen or a lower-alkyl, hydroxy-lower-alkyl, phenyl, phenyl-lower-alkyl, benzhydryl, phenyl-lower-alkenyl, cycloalkyl-lower- alkyl, or pyridyl radical; Y is lower-alkylene of from one to six carbon atoms; and Het is a 4(5)-imidazolyl radical; are disclosed.
None of the prior art teaches 4(5)-imdazolyl-substituted piperazine or diazepine derivatives substituted or useful in the manner of this invention. Compounds having the range of activity, such as those of the present invention, have remained desired.